Diarylacetylene hydrazide containing tyrosine kinase inhibitors

Abstract

The present invention relates to novel diarylacetylene hydrazide compounds of formula (I) or pharmaceutically acceptable salt thereof, as tyrosine kinase inhibitors, the process for their preparation, and to the use of the compounds of formula (I) in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders related to tyrosine kinases, in warm-blooded animals.

We claim: 
     
       1. A compound of formula (I), 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein; 
         ring P is selected from a 5 to 14 membered heteroaryl ring containing one to four hetero atoms, each independently selected from O, S and N; and ring Q is selected from an aryl ring having 6 to 14 carbon atoms, or a 5 to 14 membered heteroaryl ring containing one to four hetero atoms each independently selected from O, S and N, wherein ring P and Q are optionally substituted by one or more identical or different radicals R 3 ; 
         R 1  and R 2  are independently selected from the group consisting of hydrogen, —C 1-8 -alkyl, —C 2-10 -alkenyl, —C 2-12 -alkynyl, —C 3-12 -cycloalkyl, —C 4-12 -cycloalkylalkyl, —C 3-12 -cycloalkenyl, aryl, heteroaryl, arylalkyl and a heteroarylalkyl radical, wherein the aryl ring contains 6 to 14 carbon atoms, and the heteroaryl ring contains 5 to 14 membered ring system with one to four hetero atoms each independently selected from O, S and N, and are optionally substituted by one or more identical or different radicals R 3 ; 
         X and Y are independently selected from the group consisting of C═O and C═S ; 
         R 3  is selected from the group consisting of halogen, —OH, —CN, —NO 2 , —N 3 , —C 1-8 -alkyl, —C 3-12 -cycloalkyl, —(C 1-8 -alkyl)-C 3-12 -cycloalkyl, -heterocycloalkyl containing 3 to 12 rings atoms having one or two hetero atoms each independently selected from O, S and N, —(C 1-8 -alkyl)-heterocycloalkyl containing 3 to 12 rings atoms having one or two hetero atoms each independently selected from O, S and N, —O—C 1-8 -alkyl, —O—C 3-12 -cycloalkyl, —O-aryl, —O-heteroaryl, —C 1-8  alkyl-O—C 1-8  alkyl, —O—C 1-8  alkyl-O—C 1-8  alkyl, —O—C 1-8  alkyl-NH(C 1-8  alkyl), —O—C 1-8  alkyl-N(C 1-8  alkyl) 2 , —O—C 1-8  alkyl-(heteroaryl), —C(O)—C 1-8  alkyl, —COOH, —C(O)NH 2 , —C(O)NH—C 1-8  alkyl, —C(O)N(C 1-8  alkyl) 2 , —C(O)O—C 1-8  alkyl, —C 1-8  haloalkyl, —C 2-10  alkenyl, —C 2-12  alkynyl, —OC(O)—NH 2 , —OC(O)—NH(C 1-8  alkyl), —OC(O)—N(C 1-8  alkyl) 2 , —NH 2 , —NH(C 1-8  alkyl), —N(C 1-8  alkyl) 2 , —NH—SO 2 —C 1-8  alkyl, —N(C 1-8  alkyl)-SO 2 —C 1-8  alkyl, —NH—C(O)—(C 1-8  alkyl), —N(C 1-8  alkyl)-C(O)—(C 1-8  alkyl), —NH—C(O)O—C 1-8  alkyl, —N(C 1-8  alkyl)-C(O)O—C 1-8  alkyl, —NH—C(O)—NH 2 , —NH—C(O)—NH(C 1-8  alkyl), —N(C 1-8  alkyl)-C(O)—NH(C 1-8  alkyl), —N(C 1-8  alkyl)-C(O)—N(C 1-8  alkyl) 2 , —NH—C(O)—NH—SO 2 —C 1-8  alkyl, —N(C 1-8  alkyl)-C(O)—NHSO 2 —C 1-8  alkyl, —N(C 1-8  alkyl)-C(O)—N(C 1-8  alkyl)-SO 2 —C 1-8  alkyl, —S—C 1-8  alkyl, —S(O)—C 1-8  alkyl, —SO 2 —C 1-8  alkyl, —S-aryl, —S(O)-aryl, SO 2 -aryl, —SO 2 NH 2 , —SO 2 NH—(C 1-8  alkyl), —SO 2 N(C 1-8  alkyl) 2 ; -aryl, —(C 1-4 -alkyl)-aryl, heteroaryl or —(C 1-4 -alkyl)-heteroaryl group, wherein the aryl ring contains 6 to 14 carbon atoms, and the heteroaryl ring contains 5 to 14 membered ring system with one to four hetero atoms each independently selected from O, S and N, wherein each of the aforementioned R 3  groups may be optionally substituted with a single group selected from the group consisting of: C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -haloalkyl, —OH, —COOH, —CN, —NO 2 , halo, —NH 2  and —SO 2 NH 2 . 
       
     
     
       2. A compound according to  claim 1 , wherein ring P is selected from pyridine, thiophene, pyrazole, thiazole, quinoline, benzothiazole, pyrazine, pyrimidine, quinoxaline, quinazoline, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyridazine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyrimidine, pyrido[2,3-b]pyrazine, cinnoline, phthalazine, and ring Q is selected from phenyl, naphthyl, pyridine, thiophene, pyrazole, thiazole, quinoline, benzothiazole, pyrazine, pyrimidine, quinoxaline, quinazoline, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyridazine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyrimidine, pyrido[2,3-b]pyrazine, cinnoline, phthalazine, wherein ring P and ring Q are optionally substituted by one or more identical or different radicals R 3 . 
     
     
       3. A compound according to  claim 1 , wherein R 1  is selected from hydrogen, —C 1-8 -alkyl, —C 2-10 -alkenyl, —C 2-12 -alkynyl, —C 3-12 -cycloalkyl, —C 4-12 -cycloalkylalkyl or a —C 3-12 -cycloalkenyl group. 
     
     
       4. A compound according to  claim 1 , wherein R 2  is selected from aryl, heteroaryl, arylalkyl or a heteroarylalkyl radical, wherein the aryl ring contains 6 to 14 carbon atoms, and the heteroaryl ring contains 5 to 14 membered ring system with one to four hetero atoms each independently selected from O, S and N, and are optionally substituted by one or more identical or different radicals R 3 . 
     
     
       5. A compound according to  claim 4  wherein R 2  is an aryl or a heteroaryl ring selected from phenyl, pyridine, thiophene or pyrazole, optionally substituted by one or more identical or different radicals R 3 . 
     
     
       6. A compound according to  claim 1  wherein both X and Y are C═O. 
     
     
       7. A compound according to  claim 1  wherein X is C═S and Y is C═O. 
     
     
       8. A compound according to  claim 1  wherein R 3  is selected from the group consisting of halogen, —OH, —CN, —NO 2 , —N 3 , —C 1-8 -alkyl, —C 3-12 -cycloalkyl, —O—C 1-8  alkyl, —O—C 3-12 -cycloalkyl, —C 1-8 -haloalkyl, —(C 1-8 -alkyl)-heterocyclo alkyl containing 3 to 12 rings atoms having one or two hetero atoms each independently selected from O, S and N, aryl group, heteroaryl group, or —(C 1-4 -alkyl)-heteroaryl group, wherein the aryl ring contains 6 to 14 carbon atoms, and the heteroaryl ring contains 5 to 14 membered ring system with one to four hetero atoms each independently selected from O, S and N; wherein each of the aforementioned R 3  groups may be optionally substituted with a single group selected from the group consisting of: C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -haloalkyl, —OH, —COOH, —CN, —NO 2 , halo, —NH 2  and —SO 2 NH 2 . 
     
     
       9. A compound according to  claim 1  wherein X and Y are C═O, R 1  is hydrogen, R 2 , ring P is heteroaryl, and ring Q is aryl or heteroaryl. 
     
     
       10. A compound according to  claim 1  selected from the group consisting of
 2,4,6-Trichloro-N′-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl]benzohydrazide, 
 N′-(2-Chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide, 
 N′-(2-Iodo-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide, 
 N′-(2,6-Dichlorobenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide, 
 N′-(2-Fluoro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide, 
 2,4,6-Trichloro-N′-[3-[2-(2-imidazo[1,2-a]pyrazin-3-yl)ethynyl]-4-methylbenzoyl]benzohydrazide, 
 N′-(2-Chloro-6-methylbenzoyl)-3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methylbenzohydrazide, 
 N′-(2-Chloro-6-methylbenzoyl)-3-[2-(imidazo[1,2-a]pyrazin-3-yl)ethynyl]-4-methylbenzohydrazide, 
 N′-[2-Fluoro-6-(trifluoromethyl)benzoyl]-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide, 
 N′-(2-Chloro-6-methylbenzoyl)-4-methyl-3-[2-(quinoxalin-2-yl)ethynyl]benzohydrazide, 
 N′-(2,6-Dichlorobenzoyl)-4-methyl-3-[(imidazo[1,2-b]pyridazin-3-yl)ethynyl]benzohydrazide, 
 N′-(2-Chloro-6-methylbenzoyl)-4-methyl-3-[2-(6-fluoro-3-quinolyl)ethynyl]benzohydrazide, 
 N′-(2-Chloro-6-fluorobenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide, and a pharmaceutically acceptable salt thereof.